1. Field of the Invention
The present invention relates to a novel method and composition for treating Nonalcoholic Steatohepatitis (NASH) and Nonalcoholic Fatty Liver Disease (NAFLD). In particular, the present invention relates to the treatment of NASH and NAFLD by delivering specific naturally occurring compounds to the lower gut (colon) or rectum.
2. Description of Related Art
Butyric acid and propionic acid are naturally occurring fatty acids that occur in the form of esters in animal fats and plant oils. For example, the triglyceride of butyric acid makes up 3% to 4% of butter. Butyric acid is found in rancid foods, such as butter and cheese, and has a very unpleasant smell and taste. Butyric acid and propionic acid are important members of the fatty acid sub-group called the short-chain fatty acids.
Glutamine is natural amino acid that is used as a nutritional supplement in the treatment of a variety of diseases, including cancer. Glutamine is the most abundant free amino acid in the human body and, in addition to its role as a component of protein, it serves a variety of functions in the body. It is a non-essential amino acid because it is made by body cells. In addition, most dietary proteins contain ample amounts of glutamine and healthy people usually obtain all the additional glutamine that they need in their diet.
Glutamine, butyric acid, propionic acid and their salts are difficult to administer unformulated by the oral route to the lower gut as they are absorbed in the upper large intestine, if not degraded by stomach acids or conditions in the stomach or small intestine, first. These compounds are agonists of L-cells in the colon, which they stimulate to cause secretion of gut hormones. When dosed orally and unformulated the minimum effective amount of these compounds is 30 grams. Doses of 30 grams and more are toxic, in the case of glutamine, or unpalatable due to unpleasant smell and taste, in the case of butyrate propionate.
NASH is a common, often “silent”, liver disease. It resembles alcoholic liver disease, but occurs in people who drink little or no alcohol. The major feature in NASH is fat in the liver, along with inflammation and damage. Most people with NASH feel well and are not aware that they have a liver problem. Nevertheless, NASH can be severe and can lead to cirrhosis in which the liver is permanently damaged and scarred and no longer able to function properly.
NAFLD is a fatty liver disease common in chronic liver disease subjects. Excess liver fat can lead to liver complications. While not alcohol-related, these conditions can be related to obesity, diet, and other health-related issues.
Individuals with elevated liver enzymes and/or one having a fatty liver (e.g. determined by ultrasound or fatty liver index) are considered to have NASH or NAFLD. A reduction in enzymes, fat, or fatty liver index is an indicator of an improving or corrected condition.
There are a number of compositions designed to deliver a medicament to the lower gut. One in particular is a coating designed to release in both the pH and bacterial environment of the colon, covered by U.S. patent application Ser. No. 11/735,248, incorporated herein by reference including all related patents and applications.
A number of other formulations are available for delivery of desired compositions to the colon, including amylose-coated tablets, enterically coated chitosan tablets, matrix-within-matrix or multimatrix systems, or polysaccharide-coated tablets. One other example of multimatrix controlled-release systems is disclosed in U.S. Pat. No. 7,431,943 issued Oct. 7, 2008 to Villa et al. and incorporated herein by reference. Disclosed is a matrix-within-matrix design wherein a lipophilic phase and amphiphilic phase are incorporated within the inner matrix and at least a portion of the active ingredient is incorporated into the amphiphilic phase. Others include those described in EP 2,018,159, where a drug is released by bacteria and/or pH by removing a coating in the colon. Essentially, these compositions bind, block, encapsulate, or coat access to the drug within but are dissolved in the unique pH or bacterial environment of the colon to make a drug bioavailable in the colon.